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Interaction of CJX2, an amlodipine derivative with human P‐glycoprotein ATPase activity
Author(s) -
Ji BianSheng,
He Ling
Publication year - 2008
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.20226
Subject(s) - p glycoprotein , verapamil , chemistry , atpase , non competitive inhibition , pharmacology , biological activity , k562 cells , efflux , mechanism of action , biochemistry , enzyme , biology , cell , in vitro , calcium , multiple drug resistance , organic chemistry , antibiotics
P‐glycoprotein, a plasma membrane protein overexpressed in multidrug‐resistant (MDR) cells, is responsible for the energy‐dependent efflux of structurally unrelated cytotoxic agents and MDR‐reversing drugs from the cells. Understanding the interaction of P‐gp reversing agents with P‐gp ATPase activity should provide useful information for understanding the mechanisms of P‐gp modulator. The aim of present report was to elucidate the possible mechanism of CJX2, an amlodipine derivative, in modulating P‐gp function by determining its effect on P‐gp ATPase activity. Basal P‐gp ATPase activity in K562/DOX cells was increased by CJX2 with a half‐maximal activity concentration (K m ) of 10.7±1.8 µM. Kinetic analysis indicated a noncompetitive inhibition of verapamil (Ver)‐stimulated P‐gp ATPase activity by CJX2 and a competitive inhibition of CJX2‐stimulated P‐gp ATPase activity by tetrandrine; moreover, the effect of Cyclosporin A (CsA) on CJX2‐stimulated and Ver‐stimulated P‐gp ATPase activity showed noncompetitive and a competitive inhibition, respectively. CJX2 and Tet can bind P‐gp either on overlapping sites or distinct but interacting sites, while CJX2 and Ver as well as CsA can bind P‐gp on separate sites in K562/DOX cells. Drug Dev Res 69:42–47, 2008 © 2008 Wiley‐Liss, Inc.